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CIBIS III

CIBIS III. Results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Ronnie Willenheimer University Hospital, Malmö, Sweden, on behalf of the CIBIS III investigators. Background (1).

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CIBIS III

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  1. CIBIS III Results of the randomizedCardiac Insufficiency Bisoprolol Study (CIBIS)III Ronnie Willenheimer University Hospital, Malmö, Sweden, on behalf of the CIBISIII investigators

  2. Background (1) • Guidelines universally recommend that treatment of patients with chronic heart failure (CHF) should be initiated with an angiotensin-converting enzyme inhibitor (ACEi) to which a β-blocker should be added as second step therapy. • These recommendations are not based on evidence. • No study has examined the safety and efficacy of initiating CHF treatment with an ACEi versus a β-blocker. • Several mechanistic reasons support choosing beta-blockade as first therapy in CHF. Willenheimer et al., Circulation 2005; 112: 2426-35

  3. Background (2) • Sympathetic nervous system is activated prior to RAAS in CHF. • In the early course of CHF, sudden death is the most prevalent mode of death. • β-blockers in contrast to ACEi are proven highly effective in reducing sudden death. • From the pathophysiological point of view it may be appropriate to start with a β-blocker first. Willenheimer et al., Circulation 2005; 112: 2426-35

  4. Hypothesis Initiation of treatment in patients with CHF with the β1-selective β-blocker bisoprolol (to which enalapril is subsequently added) is as effective and safe as a regimen beginning with the ACEi enalapril (to which bisoprolol is subsequently added). Willenheimer et al., Circulation 2005; 112: 2426-35

  5. Statistical analysis Bisoprolol-first versus Enalapril-first HR 1.0 HR 1.17 superior inferior Willenheimer et al., Circulation 2005; 112: 2426-35 non-inferior not superior, not inferior, not non-inferior HR=Hazard ratio HR 1.17 = AR +5.0%

  6. Primary objective To show that initial mono-therapy with bisoprolol followed by combination therapy with enalapril is comparable (non-inferior) to the reverse order in preventing death and hospitalization for all causes (combined endpoint). Willenheimer et al., Circulation 2005; 112: 2426-35

  7. Secondary objectives • To compare the primary and secondary endpoints • in terms of superiority for bisoprolol-first. Willenheimer et al., Circulation 2005; 112: 2426-35

  8. Endpoints • Primary endpoint • Combined endpoint of mortality (all cause) and all cause hospitalization throughout the study period (time to event analysis) • Secondary endpoints • End of monotherapy phase • Combined endpoint of all-cause mortality and hospitalization • Early introduction of the second drug due to poor control of CHF • End of monotherapy phase + end of study • Individual components of the primary endpoint • Number of permanent treatment cessations • Changes in NYHA class Willenheimer et al., Circulation 2005; 112: 2426-35

  9. Study design (1) Bisoprolol-first (o.d.) 10.0 mg 5.0 2.5 Enalapril b.i.d. 10.0 mg 7.5 5.0 3.75 2.5 1.25 Bisoprolol o.d. Bisoprolol o.d. First up-titration Maintenance period Second up-titration Second maintenance period 22-100 weeks * * * * * * * * * * * * * * * * ……….……. * * * * * week Study end 0 2 4 6 8 10 26 28 30 32 34 36 1 - 2.5 years * = visits 10.0 mg 7.5 5.0 3.75 Enalapril-first (b.i.d.) 2.5 Willenheimer et al., Circulation 2005; 112: 2426-35 1.25 Bisoprolol o.d. 10.0 mg 5.0 2.5 Enalapril b.i.d Enalapril b.i.d First up-titration Second up-titration Second maintenance period Maintenance period 16-94 weeks * * * * * * * * * * * * * * * * ……….……. * * * * * week Study end 0 2 4 6 8 10 26 28 30 32 34 36 1 - 2.5 years

  10. Study design (2) • Investigator-initiated, multi-center, prospective, randomized, open-label, blinded endpoint evaluation (PROBE) trial • Independent • steering committee • data safety monitoring board • masked endpoint committee • clinical trial data center Willenheimer et al., Circulation 2005; 112: 2426-35

  11. Inclusion criteria • Age >= 65 years • Mild to moderate CHF (NYHA class II or III) • LVEF <= 35% • Stable CHF since >= 7 days • (without clinically relevant fluid retention/diuretic adjustment) Willenheimer et al., Circulation 2005; 112: 2426-35

  12. Exclusion criteria • > 7 days ACEi, ARB or β-blocker within last 3 months • PTCA or bypass surgery planned or performed within last 3 months • Stroke within 1 month or with permanent neurological damage within last 6 months • Resting heart rate < 60 beats per minute (without a pacemaker) • Resting SBP < 100mm Hg • Serum creatinine >= 220 μmol/l • > 1st degree AV-block without a pacemaker • Chronic obstructive lung disease, which would contraindicate bisoprolol at the discretion of the investigator Willenheimer et al., Circulation 2005; 112: 2426-35

  13. Participating Countries 128 centers in 20 countries • Poland • Sweden • Norway • Slovakia • UK/Ireland • Russia • Croatia • Hungary • Romania • Austria • Belgium • Switzerland • Czech Republic • France • Germany • The Netherlands • Italy • Portugal 1010 patients Tunisia Willenheimer et al., Circulation 2005; 112: 2426-35 Australia 5 pts LTFU 3 bisoprolol-first 2 enalapril-first October 2002 - May 2005

  14. Baseline data Bisoprolol-first (n=505) Mean / n % / SD Enalapril-first (n=505) Mean / n % / SD Age (years) Males 72.4 333 5.8 65.9 72.5 356 5.7 70.5 NYHA Class II/III 245 / 260 48.5 / 51.5 250 / 255 49.5 / 50.5 LVEF (%) 28.8 4.8 28.8 5.2 Heart rate (bpm) BP (mm Hg) Etiology CAD Hypertension Diabetes 78.8 134 / 80 309 197 95 13.8 17 / 10 61.2 39.0 18.8 79.5 134 / 81 321 172 113 13.2 17 / 10 63.6 34.1 22.4 Willenheimer et al., Circulation 2005; 112: 2426-35 Diuretic treatment Loop diuretics Aldo rec blockers Cardiac glycosides 430 361 72 166 85.1 71.5 14.3 32.9 421 338 62 155 83.4 66.9 12.3 30.7

  15. Primary endpoint (1) % without endpoint Per-protocol (PP) Bisoprolol-first 100 Enalapril-first 90 80 70 For non-inferiority P<0.025 denotes statistical significance (unilateral test) 60 B/E vs E/B HR 0.97 (95% CI 0.78-1.21) non-inferiority P=0.046 Willenheimer et al., Circulation 2005; 112: 2426-35 Mean follow-up 1.25 years 50 months 0 6 12 18 Patients at risk 265 259 503 498 356 353 80 73

  16. Primary endpoint (2) % without endpoint Intention-to-treat (ITT) Bisoprolol-first 100 Enalapril-first 90 80 70 For non-inferiority P<0.025 denotes statistical significance (unilateral test) 60 B/E vs E/B HR 0.94 (95% CI 0.77-1.16) non-inferiority P=0.019 Willenheimer et al., Circulation 2005; 112: 2426-35 Mean follow-up 1.25 years 50 0 6 12 18 months Patients at risk 505 505 389 388 87 76 291 277

  17. All-cause hospitalization throughout study (ITT) % without hospitalization Bisoprolol-first Enalapril-first 100 90 80 70 B/E vs E/B HR 0.95 (95% CI 0.76-1.19) P=0.66 (difference) 60 Willenheimer et al., Circulation 2005; 112: 2426-35 50 months 0 6 12 18 Numbers at risk 505 386 289 85 505 387 277 76

  18. All cause mortality throughout study (ITT) Bisoprolol-first % survival Enalapril-first 100 95 90 85 B/E vs E/B HR 0.88 (95% CI 0.63-1.22) P=0.44 (difference) 80 Willenheimer et al., Circulation 2005; 112: 2426-35 75 months 0 6 12 18 Numbers at risk 475 379 117 505 470 368 125 505

  19. Primary endpoint at end of monotherapy (ITT) (all cause mortality and all cause hospitalization) % without endpoint Bisoprolol-first Enalapril-first 100 95 90 B/E vs E/B HR 1.02 (95% CI 0.78-1.33) P=0.90 (difference) 85 Willenheimer et al., Circulation 2005; 112: 2426-35 80 months 0 1 2 3 4 5 6 Numbers at risk 505 469 434 414 400 383 195 505 473 437 410 396 376 213

  20. Hospitalization (all cause) at end of monotherapy (ITT) % without endpoint Bisoprolol-first Enalapril-first 100 95 90 B/E vs E/B HR 1.08 (95% CI 0.81-1.43) P=0.59 (difference) 85 Willenheimer et al., Circulation 2005; 112: 2426-35 80 months 0 1 2 3 4 5 6 Numbers at risk 505 467 432 413 397 381 193 505 471 433 407 395 376 213

  21. All cause mortality up to 1 year (ITT) % survival Bisoprolol-first Enalapril-first 100 95 90 85 B/E vs E/B HR 0.69 (95% CI 0.46-1.02) P=0.06 (difference) 80 Willenheimer et al., Circulation 2005; 112: 2426-35 75 months 0 6 12 475 379 Numbers at risk 505 470 368 505

  22. All cause mortality at end of monotherapy (ITT) % survival Bisoprolol-first Enalapril-first 100 95 90 B/E vs E/B HR 0.72 (95% CI 0.42-1.24) P=0.24 (difference) 85 Willenheimer et al., Circulation 2005; 112: 2426-35 80 months 0 1 2 3 4 5 6 Numbers at risk 495 481 463 453 446 234 505 492 473 458 448 434 254 505

  23. Worsening heart failure (ITT)Requiring hospitalization or occurring in hospital % without endpoint Bisoprolol-first Enalapril-first 100 95 90 85 B/E vs E/B HR 1.25 (95% CI 0.87-1.81) P=0.23 (difference) 80 Willenheimer et al., Circulation 2005; 112: 2426-35 75 months 0 6 12 18 Numbers at risk 505 434 342 103 505 444 346 111

  24. Bisoprolol-first Enalapril-first 39 (7.7%) 37 (7.3%) 35 (6.9%) 49 (9.7%) 19 (3.8%) 24 (4.7%) 47 (9.3%) 16 (3.2%) 101 (20.0%) 89 (17.6%) Other secondary endpoints (ITT) P 0.81 0.11 0.37 <0.001 0.33 Early introduction of second drug Permanent treatment cessation Monotherapy phase Combination phase ( Biso) Willenheimer et al., Circulation 2005; 112: 2426-35 ( Enal) Total

  25. Subgroups: primary endpoint II NYHA III Female Gender Male <72 Age (years) >72 P=0.001 <28 LVEF % >28 Yes Diabetes No Yes Hypertension No <80 Heart rate (beats/min) > 80 Systolic BP (mm Hg) < 140 Willenheimer et al., Circulation 2005; 112: 2426-35 >140 < 11.5 Haemoglobin (g/dl) >11.5-16 >16 Creatinine clearance <60 > 80 (ml/min) Yes Cardiac glycosides No 0.0 0.5 1.0 1.5 2.0 2.5 Bisoprolol-first better Enalapril-first better

  26. Bisoprolol-first (n=504) Enalapril-first (n=502) Number (%) of patients reporting Number of reports Number (%) of patients reporting Number of reports Monotherapy phase SAEs 113 (22.4) 192 111 (22.1) 163 AEs 316 (62.7) 813 319 (63.5) 861 Entire study period SAEs 184 (36.5) 360 187 (37.3) 354 AEs 396 (78.6) 1589 395 (78.7) 1769 Safety Willenheimer et al., Circulation 2005; 112: 2426-35 All P=NS

  27. Conclusions (1) In terms of combined mortality / hospitalization Bisoprolol-first was non-inferior to enalapril-first in the ITT sample Bisoprolol-first was close to non-inferior to enalapril-first in the PP sample Willenheimer et al., Circulation 2005; 112: 2426-35

  28. Bisoprolol-first Enalapril-first 86% 72% Bisoprolol >= 5 mg x 1 P<0.001 82% 90% Enalapril >= 5 mg x 2 P<0.001 Last prescribed study drug dose>= 50% of target dose Willenheimer et al., Circulation 2005; 112: 2426-35

  29. Conclusions (2) • There was no difference in safety between the two strategies, • showing that a bisoprolol-first strategy does not cause concerns Willenheimer et al., Circulation 2005; 112: 2426-35

  30. Thoughts for the future (1) Bisoprolol-first achieved clinically comparable survival and all-cause hospitalization compared with enalapril-first. % event-free Primary endpoint PP 100 B / E 90 E / B 80 Willenheimer et al., Circulation 2005; 112: 2426-35 70 60 50 40 Time (months) 18 12 0 6

  31. Thoughts for the future (3) Bisoprolol-first showed a trend towards improved survival during the early study phase (which was maintained during combined therapy). % event-free All cause mortality at end of monotherapy phase 100 95 Willenheimer et al., Circulation 2005; 112: 2426-35 90 B / E E / B 85 80 75 Time (months) 0 1 2 3 4 5 6

  32. Thoughts for the future (2) Bisoprolol-first was associated with a trend towards increased worsening of CHF in the early phase of treatment. % event-free Worsening of CHF throughout study 100 B / E E / B 95 90 Willenheimer et al., Circulation 2005; 112: 2426-35 85 80 75 70 Time (months) 18 0 6 12

  33. Thoughts for the future (4) • Bisoprolol-first might increase survival in the early phase of treatment, allowing a greater number of patients to subsequently benefit from combined β-blocker + ACEi. • The bisoprolol-first strategy could be further improved with greater experience of up-titration of the β-blocker-first, leading to less worsening of CHF. • This should be further examined. Willenheimer et al., Circulation 2005; 112: 2426-35

  34. Clinical implication The CIBIS III result supports a free choice of initial treatment for CHF - enalapril or bisoprolol - based on the physician’s individual judgment in each patient Willenheimer et al., Circulation 2005; 112: 2426-35

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